: The overall objective of this application is to determine by which types of mechanisms antibody (Ab) protects against or reduces influenza-associated morbidity, how specificity, heavy chain isotype and avidity affect its protective activity and how activities provided by memory T cell responses enhance it. The studies are conducted in the mouse influenza model system. The basic experimental approach is to measure the effects of passive Abs on the course of the infection in various knockout mouse strains. The application has four major aims. The first is to determine how important the concomitant action of neutralization of progeny-virus (VN activity) and inhibition of release of progeny virus from infected cells (cell targeting, CT activity) is for effective Ab-mediated clearance of an established infection. This will be investigated by topical treatment of infected SCID mice with combinations of F(ab) and intact Ab reagents, which mediate solely VN or CT activity, respectively. Second, the effect of heavy chain isotype on Ab-mediated VN and CT activity in vivo will be determined by means of switch variants. In addition, Fc-dependent mechanisms involved in Ab mediated VN and CT activity will be identified by measuring the protective activity of passive Abs in mouse strains with deleted complement factor C3 and various Fcgamma receptors. Further, the reason for the previously reported low therapeutic efficacy of polymeric IgM and IgA will be determined. Third, the effect of Ab avidity on its protective activity in vivo will be investigated. Fourth, synergistic activities between Ab and CD4+ memory T cell responses will be explored by measuring the effect of passive Ab on the course of the infection in immune CD8+ cells depleted (B cell-deficient) uMT mice. Synergistic interactions between Ab and CD4+ T cell-mediated activities will be further investigated by adoptive transfer of CD4+ virus-specific T cell clones/populations and Ab into infected SCID mice. These studies will greatly improve our understanding of the mechanisms involved in Ab-mediated protection against influenza and may lead to new methods for decreasing the still very high influenza-associated severe morbidity and mortality in humans with underlying risk factors like age (>65y), diabetes and chronic lung, cardiovascular and renal diseases.